Pulmonary macrophages (PAM) may be the most important primary defense system protecting the lung from microbial invasions and inhaled pollutants as well as from neoplastic growth. We have demonstrated that development of "resident" PAM in the lungs is the result of exogenous antigenic (nonspecific) stimulation. Although the absolute number of PAM in the lungs of germfree (GF) piglets was considerably less than that found in the lungs of specific pathogen-free (SPF) piglets, the PAM from GF and SPF animals were functionally equivalent in that they were equally able to mediate antibody-dependent cellular cytotoxicity (ADCC) and immobilized immune, complex-dependent cellular cytotoxicity (IIC-DCC). We have also found that PAM have a self-recognition mechanism to avoid autocytotoxicity even in the presence of phytohemagglutin which mediate cytotoxicity towards xenogeneic targets. However, we have discovered that PAM are capable of being nonspecifically cytotoxic toward autologous as well as xenogeneic cells when the Fc receptors are modulated by immobilized immune complexes (IIC) or immune complexes (IC) in suspension in conjunction with cytochalasin B so that they are unable to internalize these activated receptors. We have investigated the cytolytic mechanisms of PAM involved in ADCC and IICDCC. The results indicate that IIC-DCC was inhibited by both catalase and thioglycollate broth while these peroxide scavengers had no effect on ADCC. These data show that the lytic mechanism involved in the nonspecific cytotoxicity generated by exposing PAM to IIC or IC in suspension in conjunction with cytochalasin B is mediated solely by peroxide while the lytic mechanism involved in ADCC operates, at least partially, through a peroxide-independent mechanism. The ability of PAM to secrete prostaglandin E (PGE) and become nonspecifically cytotoxic to autologous target cells in response to exposure to IIC was compared. PAM exposed to IIC secrete more PGE than PAM exposed to IC in suspension, and PGE secretion and IIC-DCC mediated by modulation of the Fc receptor appears to be independent functions, since drugs which inhibit PGE synthesis have little effect on nonspecific cytotoxicity.PGE secretion as well as nonspecific cytotoxicity by macrophages may contribute to the pathogenesis of disease states where antibodies are directed against immobilized self antigens or microbial antigens on immobilized tissue. Investigations on ontogenic development, differentiation, and functions of PAM and regulatory mechanisms of their cytolytic effector functions may lead to manipulation or control of the vital pulmonary defense system to confer a better survival advantage. (MB)